Assessment and improvement of treatment using imaging of physiological responses to radiation therapy

ABSTRACT

Edema in tissue of a patient undergoing a course of radiation therapy or treatment can be estimated based on one or more MRI measurements used to measure changes in fluid content of various tissues. A correlation between observed changes in edema and one or more delivered fractions of radiation can be used to drive one or more clinical actions. Methods, systems, articles of manufacture, and the like are described.

CROSS-REFERENCE TO RELATED APPLICATIONS

The current application is a continuation of and claims priority under35 U.S.C. § 120 to U.S. patent application Ser. No. 15/851,543, filedDec. 21, 2017, which claims priority under 35 U.S.C. § 120 to U.S.patent application Ser. No. 14/064,053, filed Oct. 25, 2013, whichclaims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application61/719,337, which was filed on Oct. 26, 2012, the disclosures of eachare incorporated by reference in its entirety.

TECHNICAL FIELD

The subject matter described herein relates to radiation therapy and toMRI imaging of physiological responses to radiation therapy, such as forexample edema, etc.

BACKGROUND

Radiation therapy maintains a unique and established role among thethree major forms of cancer therapy (surgery, chemotherapy, andradiation therapy). Surgery removes cancer-laden tissues from the body,destroying them. Chemotherapy sterilizes microscopic disease throughoutthe entire body. Only radiation therapy can both destroy canceroustissues and sterilize microscopic disease simultaneously. Experimentalablative cancer treatment technologies (e.g., ultrasound, hyperthermia,and cryosurgery) can only destroy tissue like surgery, while novelchemotherapy agents cannot effectively destroy solid tumors. Radiationtherapy will maintain and expand its prominent role as the treatment ofchoice in cancer therapy and ablative therapies.

The clinical objective of radiation therapy is to accurately deliver anoptimized ionizing radiation dose distribution to the tumor and targetswhile sparing the dose to the surrounding normal tissue. In deliveringionizing radiation, the clinician attempts to make a trade off betweenthe probability that the disease will be eradicated and the probabilitythat a deadly or debilitating side effect will occur from theirradiation of the surrounding healthy or functional tissues.

Whether ablating or sterilizing tissues, ionizing radiation kills cellsby breaking chemical bonds in DNA or other important molecules in thecell. Radiation therapy functions by targeting rapidly dividing cancercells, where the radiation causes a reaction that damages the DNA orother important molecules in the cell, causing cell death at celldivision. Cancer cells, unlike normal cells, divide rapidly and can'trepair themselves easily, and as a result of the genetic damage from theradiation, they die more readily than healthy cells. Extending thetreatment over time and delivering the dose in fractions allows healthycells to recover while tumor cells are preferentially eliminated.Sometimes, less recovery of healthy cells can be accepted if greaterpositioning and immobilization accuracy can be attained usingstereotactic methods.

The use of ionizing radiation therapy to treat cancer or ablate tissuesworks by damaging the DNA or other critical molecules of cancerous ortargeted cells. This DNA damage is caused when ionizing chargedparticles cause direct or indirect ionization of the atoms, which makeup the DNA chain or other important cellular molecules. Directionization occurs when the atoms of DNA or other critical cellularmolecules are directly produced by the impinging radiation. Indirectionization occurs as a result of the ionization of the aqueous cellularcomponent, forming free radicals, which then damage the DNA or othercritical cellular molecules. Cells have mechanisms for repairingsingle-strand DNA damage and thus double-stranded DNA breaks are themost significant mechanism for causing cell death. Cancer cells aregenerally undifferentiated and stem cell-like, which causes them toreproduce more than most healthy differentiated cells, and also to havea diminished ability to repair sub-lethal damage. Single-strand DNAdamage is then passed on through cell division and damage to the cancercells' DNA accumulates, causing them to die or reproduce more slowly.

Radiosensitivity is the relative susceptibility of cells, tissues,organs or organisms to the harmful effect of ionizing radiation. Thereare four major modifiers of radiosensitivity, which are typicallyreferred to as “4 R's”: re-oxygenation, re-assortment of the cell-cycle,repair of sublethal damage, and repopulation.

Tumors contain regions of hypoxia (low aqueous oxygen concentration) inwhich cancer cells are thought to be resistant to radiation. Duringfractionated radiotherapy, these regions are reoxygenated by variousmechanisms including reduction of intratumoral pressure andnormalization of the vasculature. Reoxygenation between radiationfractions leads to radiosensitization of previously hypoxic tumor areasand is thought to increase the efficiency of radiation treatment.

Mammalian cells exhibit different levels of radioresistance during thecourse of the cell cycle. In general, radiation has a greater effect oncells with a greater reproductive activity. Cells in the late S-phaseare especially resistant and cells in the G2-phase and M-phase are mostsensitive to ionizing radiation. During fractionated radiation, cells inthe G2M-phase are preferentially killed. The time between two fractionsallows resistant cells from the S-phase of the cell cycle toredistribute into phases in which cells are more radiosensitive.

Cell kill by ionizing radiation is based on production of unrepairablelesions involving DNA double-strand breaks (DSBs) or damage of othercritical molecules. Most radiation-induced DNA damage is howeversublethal. Although this damage is generally repaired at lower doses, athigher doses accumulation of sublethal lesions also contributes tolethality. Repair of sublethal damage between radiation fractions isexploited in radiation therapy because critical normal tissues andtumors often differ in their ability to repair radiation damage.

Normal and malignant stem cells have the ability to perform asymmetriccell division, which results in a daughter stem cell and a committedprogenitor cell. In contrast, stem cells divide into two committedprogenitor cells or two daughter stem cells in a symmetric celldivision. If the latter happens only in 1% of the stem cell divisions,the number of stem cells after 20 cell doublings will be twice as highas the number of committed progenitor cells. As such, small changes inthe way stem cells divide can have a huge impact on the organization ofa tissue or tumor and are thought to be the mechanism behind acceleratedrepopulation.

Quickly dividing tumor cells and tumor stem cells are generally(although not always) more sensitive than the majority of body cells.The 4 R's mentioned above can have a significant impact on theradiosensitivity of both tumor and healthy cells, which can be, forexample, hypoxic and therefore less sensitive to X-rays that mediatemost of their effects through free radicals produced by ionizing oxygen.

The most sensitive cells are those that are undifferentiated, wellnourished, quickly dividing, and highly metabolically active. Amongstthe body cells, the most sensitive are spermatogonia and erythroblasts,epidermal stem cells, and gastrointestinal stem cells. The leastsensitive are nerve cells and muscle fibers. Very sensitive cells alsoinclude oocytes and lymphocytes, although they are resting cells andthus do not meet the criteria described above.

The damage of the cell can be lethal (the cell dies) or sublethal (thecell can repair itself). The effects on cells can be deterministicand/or stochastic.

Deterministic effects have a threshold of irradiation under which theydo not appear and are the necessary consequence of irradiation. Thedamage caused by deterministic effects generally depends on the dose.Such effects are typically sublethal (e.g., they produce a lesspronounced form of disease) in a dose rage between about 0.25 to 2 Sv(Sieverts), and lethal (e.g., a certain percent of the population dieswithin 60 days) in a dose rage between about 2 to 5 Sv. Dose above about5 Sv cause the majority of people to die within 60 days, and those above6 to 7 Sv cause all people to die. Of course, the specific effects onany one person also depend on other factors, such as for example age,sex, health etc.

Stochastic or random effects, which can be classified as either somaticor genetic effects, are coincidental and cannot be avoided. Such effectsalso do not have a threshold. Among somatic effects, secondary cancer isthe most important. Secondary cancer generally develops becauseradiation causes DNA mutations directly and indirectly. Direct effectsare those caused by ionizing particles and rays themselves, while theindirect are those that are caused by free radicals, generatedespecially in water radiolysis and oxygen radiolysis. The geneticeffects confer the predisposition of cancer to the offspring.

The response of a type of cancer cell to radiation is described by itsradiosensitivity. Highly radiosensitive cancer cells are rapidly killedby modest doses of radiation. Such cancer cells include leukemias, mostlymphomas, and germ cell tumors. The majority of epithelial cancers areonly moderately radiosensitive, and require a significantly higher doseof radiation, such as for example approximately 60 to 70 Gy (Grays) toachieve a radical cure. Some types of cancer are notably radioresistant,that is, much higher doses are required to produce a radical cure thanmay be safe in clinical practice. Renal cell cancer and melanoma aregenerally considered to be radioresistant.

The response of a tumor to radiation therapy can also be related to asize of the tumor. For complex reasons, very large tumors respond lesswell to radiation than smaller tumors or microscopic disease. Variousstrategies can be used to overcome this effect. The most commontechnique is surgical resection prior to radiation therapy. Thisapproach is most commonly seen in the treatment of breast cancer withwide local excision or mastectomy followed by adjuvant radiationtherapy. Another method involves shrinking the tumor with neoadjuvantchemotherapy prior to radical radiation therapy. A third techniqueinvolves enhancing the radiosensitivity of the cancer by giving certaindrugs during a course of radiation therapy. Examples of radiosensitizingdrugs include, but are not limited to Cisplatin, Nimorazole, Cetuximab,and the like.

Radiation therapy is itself painless to the patient. Many low-dosepalliative treatments (for example, radiation therapy to bonymetastases) cause minimal or no side effects, although short-term painflare-up can be experienced in the days following treatment due to edemacompressing nerves in the treated area. Higher doses can cause varyingside effects during treatment (acute side effects), in the months oryears following treatment (long-term side effects), or afterre-treatment (cumulative side effects). The nature, severity, longevity,etc. of side effects depend on the radiosensitivity of organs thatreceive the radiation, the treatment itself (type of radiation, dose,fractionation, concurrent chemotherapy), and the patient. Side effectsfrom radiation are usually limited to the area of the patient's bodythat is under treatment.

The major side effects observed in the current art of radiation therapyare fatigue and skin irritation. The fatigue often sets in during themiddle of a course of treatment and can last for weeks after treatmentends. The irritated skin will heal, but may not be as elastic as it wasbefore. Many acute side effects are also observed.

Acute side effects are induced either immediately or soon aftercommencement of irradiation. Such effects can include swelling (alsoreferred to as edema or oedema), nausea and vomiting, damage toepithelial surfaces, mouth and throat sores, intestinal discomfort,infertility, and the like. Late effects occur months to years aftertreatment and are generally limited to the area that has been treated.They are often caused by damage of blood vessels and connective tissuecells. Severity of late effects can be reduced by fractionatingtreatment into smaller parts. The damaged and dying cells in an organwill signal and produce an inflammatory response to ionizing radiation,which is the underlying cause of many of the acute effect listed below.

As part of the general inflammation that occurs from radiation damage ofcells, swelling of soft tissues may cause problems during radiationtherapy. This acute effect can be a concern during treatment of braintumors and brain metastases, especially where there is pre-existingraised intracranial pressure or where the tumor is causing near-totalobstruction of a lumen (e.g., trachea or main bronchus). Surgicalintervention may be considered prior to treatment with radiation. Ifsurgery is deemed unnecessary or inappropriate, the patient may receivesteroids during radiation therapy to reduce swelling.

Nausea and vomiting are typically associated only with treatment of thestomach or abdomen (which commonly react a few hours after treatment),or with radiation therapy to certain nausea-producing structures in thehead during treatment of certain head and neck tumors, most commonly thevestibules of the inner ears. As with any distressing treatment, somepatients vomit immediately during radiotherapy, or even in anticipationof it, but this 1s considered a psychological response. Nausea for anyreason can be treated with antiemetics.

Epithelial surfaces may sustain damage from radiation therapy. Dependingon the area being treated, this may include the skin, oral mucosa,pharyngeal, bowel mucosa, ureter, etc. The rates of onset of damage andrecovery from such damage depend upon the turnover rate of epithelialcells. Typically, the skin starts to become pink and sore several weeksinto treatment. This reaction may become more severe during thetreatment and for up to about one week following the end of radiationtherapy, and the skin may break down. Although this moist desquamationis uncomfortable, recovery is usually quick. Skin reactions tend to beworse in areas where there are natural folds in the skin, such asunderneath the female breast, behind the ear, and in the groin.

If the head and neck area is treated, temporary soreness and ulcerationcan commonly occur in the mouth and throat. If severe, these effects canaffect swallowing, and the patient may need painkillers and nutritionalsupport/food supplements. The esophagus can also become sore if it istreated directly, or if, as commonly occurs, it receives a dose ofcollateral radiation during treatment of lung cancer.

The lower bowel may be treated directly with radiation (treatment ofrectal or anal cancer) or be exposed by radiation therapy to otherpelvic structures (prostate, bladder, female genital tract). Typicalsymptoms can include soreness, diarrhea, and nausea.

The gonads (ovaries and testicles) are very sensitive to radiation. Theymay be unable to produce gametes following direct exposure to mostnormal treatment doses of radiation. Treatment planning for all bodysites is designed to minimize, if not completely exclude, dose to thegonads if they are not the primary area of treatment. Infertility can beefficiently avoided by sparing at least one gonad from radiation.

Over the long term, other morphological changes due to cell death andradiation denaturing or damaging of tissues will appear as late sideeffects, such as for example fibrosis, epilation, dryness, lymphedema,cancer, heart disease, cognitive decline, radiation proctitis, etc.

Fibrosis refers to irradiated tissues tending to become less elasticover time due to a diffuse scarring process. Epilation (hair loss) mayoccur on any hair bearing skin with doses above 1 Gy. It only occurswithin the radiation field/s. Hair loss may be permanent with a singledose of 10 Gy, but if the dose is fractionated permanent hair loss maynot occur until dose exceeds 45 Gy.

The salivary glands and tear glands have a radiation tolerance of about30 Gy in 2 Gy fractions, a dose which is exceeded by most radical headand neck cancer treatments. Dry mouth (xerostomia) and dry eyes(xerophthalmia) can become irritating long-term problems and severelyreduce the patient's quality of life. Similarly, sweat glands in treatedskin (such as the armpit) tend to stop working, and the naturally moistvaginal mucosa is often dry following pelvic irradiation.

Lymphedema, a condition of localized fluid retention and tissueswelling, can result from damage to the lymphatic system sustainedduring radiation therapy. It is the most commonly reported complicationin breast radiation therapy patients who receive adjuvant axillaryradiotherapy following surgery to clear the axillary lymph nodes.

Radiation, while used to treat cancer, is at the same time a potentialcause of cancer, and secondary malignancies are seen in a very smallminority of patients—usually less than 1/1000. Cancers resulting fromradiation treatments typically arise 20 to 30 years following treatment,although some haematological malignancies may develop within 5 to 10years. In the vast majority of cases, this risk is greatly outweighed bythe reduction in risk conferred by treating the primary cancer. Newcancers resulting from radiation treatment typically occur within thetreated area of the patient.

Radiation has potentially excess risk of death from heart disease seenafter some past breast cancer radiation therapy regimens.

In cases of radiation applied to the head radiation therapy may causecognitive decline. Cognitive decline was especially apparent in youngchildren, between the ages of 5 to 11. Studies found, for example, thatthe IQ of 5 year old children declined each year after treatment byseveral IQ points.

Radiation proctitis can involve long-term effects on the rectum,including one or more of bleeding, diarrhoea and urgency, and isgenerally associated with radiation therapy to pelvic organs. Pelvicradiation therapy can also cause radiation cystitis when the bladder isaffected.

SUMMARY

In one aspect, a method includes comparing a subsequent edema analysisperformed after or during at least part of a course of radiationtreatment to a baseline edema analysis (performed previous to thesubsequent edema analysis to estimate a change in edema in patienttissues resulting from the course of radiation treatment, deriving anedema to delivered dose correlation based at least in part on the changein edema in the patient tissue correlated with a delivered dose ofradiation during the course of radiation treatment, and performing oneor more clinical actions based on the edema to delivered dosecorrelation.

In some variations one or more of the following can optionally beincluded. The subsequent edema analysis and baseline edema analysis caneach include at least one of an MRI scan, a T₁-weighted MRI scan, aT₂-weighted MRI scan, a ratio of T₁-weighted MRI to T₁-weighted MRI scanresults, and an MRI response ratio. For example, the subsequent edemaanalysis can include a subsequent MRI scan and the baseline edemaanalysis comprises a baseline MRI scan. Alternatively or in addition,the subsequent edema analysis can include a subsequent ratio of asubsequent T₁-weighted scan and a subsequent T₂-weighted MRI scan andthe baseline edema analysis comprises a ratio of a baseline T₁-weightedand a baseline T₁-weighted MRI scan.

The comparing can include quantifying changes in free hydrogen contentin the patient tissues as a proxy for the change in edema, and thequantifying can include performing a differential analysis of thesubsequent edema analysis and the baseline edema analysis to derive arelative amount of free hydrogen as a function of location in thepatient tissue. The deriving of the edema to delivered dose correlationcan include applying one or more calculations or models of physical dosedelivery to derive one or more of an amount of radiation actuallydelivered to the patient tissue and an expected amount of radiationdelivered to the patient tissue. The derived amount of radiationactually delivered or expected to have been delivered can be based atleast in part on one or more inputs comprising a pre-radiation treatmentplan and/or on a combined MRI and radiation delivery approach thatcalculates received doses of radiation based on intra-fraction motionsof the patient tissue.

The method can further include correlating the change in edema in thepatient tissue with the delivered dose. The correlating can includequantifying how the change in edema corresponds to an expected outcomefor the diseased tissue and surrounding tissues relative to an expectedvalue. The expected value can be calculated using at least one ofempirical, experimental, and theoretical modeling approaches. The one ormore clinical actions based on the edema to delivered dose correlationcan include at least one of stopping the course of treatment for furtheranalysis, alerting a clinician, increasing an amount of radiationdelivered in a later fraction of the course of treatment, and reducingan amount of radiation delivered in the later fraction of the course oftreatment.

Systems and methods consistent with this approach are described as wellas articles that comprise a tangibly embodied machine-readable mediumoperable to cause one or more machines (e.g., computers, etc.) to resultin operations described herein. Alternatively, hardware, including butnot limited to digital electronic circuitry, integrated circuitry,specially designed application specific integrated circuits (ASICs),field programmable gate arrays (FPGAs) computer hardware, firmware,software, computing systems, and/or combinations thereof, can beconfigured to perform one or more operations described herein. Acomputing system may include a programmable processor, such as forexample a general purpose processor and a memory coupled to theprocessor. The memory may include one or more programs that cause theprogrammable processor to perform one or more of the operationsdescribed herein.

The details of one or more variations of the subject matter describedherein are set forth in the accompanying drawings and the descriptionbelow. Other features and advantages of the subject matter describedherein will be apparent from the description and drawings, and from theclaims.

DESCRIPTION OF DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of this specification, show certain aspects of the subject matterdisclosed herein and, together with the description, help explain someof the principles associated with the disclosed implementations. In thedrawings,

FIG. 1 shows a schematic diagram of a radiation therapy system;

FIG. 2 shows a schematic diagram illustrating a demonstration of gantryrotation;

FIG. 3 shows a schematic diagram illustrating a top view of the systemshown in FIG. 1;

FIG. 4 shows a schematic diagram illustrating a side view of the systemshown in FIG. 1;

FIG. 5 shows a detailed schematic of a co-registered isotopic radiationsource with a multi-leaf collimator, such as for example that shown inFIG. 1 through FIG. 4;

FIG. 6 shows a first MRI scan image illustrating a T₁-weighted scanresult;

FIG. 7 shows a second MRI scan image illustrating a T₂-weighted scanresult;

FIG. 8 shows a process flow diagram illustrating aspects of a methodhaving one or more features consistent with implementations of thecurrent subject matter; and

FIG. 9 shows a diagram illustrating features of a system consistent withimplementations of the current subject matter.

When practical, similar reference numbers denote similar structures,features, or elements.

DETAILED DESCRIPTION

Physiological changes that occur in tissues due to ionizing radiationcreate changes that can be detected with magnetic resonance imaging(MRI) as changes in anatomic morphology and signal intensity. In theprior, diagnostic art of MRI, these changes are generally considered tobe impediments to further diagnosis and follow up and are described toavoid misinterpretation in a MRI diagnostic study. As an example, see“MRI appearance of radiation-induced changes of normal cervicaltissues,” Nömayr A, Lell M, Sweeney R, Bautz W, Lukas P. Eur Radiol.2001; 11(9):1807-17.

In contrast, implementations of the current subject matter treat thesechanges are not merely impediments to proper radiologic diagnosis, butrather as useful tools in the assessment and improvement of radiationtreatment techniques.

In currently available approaches, assessments of the probability that adisease under radiation treatment will be eradicated by radiotherapy orthat a side effect will occur typically involves evaluating dose-volumeinformation derived from a patient treatment plan. Changes in patientgeometry and anatomy can cause the delivered dose to differ from theplanned dose. As described in co-owned U.S. Pat. No. 7,907,987,improvements in radiation treatment can include accounting for thepresence of patient motions and changes over the course of a radiationtherapy delivery regime, for example by incorporating real-timesimultaneous magnetic resonance imaging (MRI) into the radiationdelivery process. The microenvironment of the tumor and healthy tissuesbeing irradiated can also be influenced by the 4R's discussed above.However, effective and practical methods of in vivo assessment of suchphysiological reactions to radiotherapy have not previously existed.

The current subject matter includes approaches to acquiring, evaluating,and incorporating additional MRI data that can be obtained during acourse of radiation therapy to improve a clinician's ability to assessthe probability that the disease under radiation treatment will beeradicated or that a side effect will occur in a given patient that isundergoing radiation therapy. The assessment can be based at least inpart on the measurement of physiological and morphological changes inthe patient's tissues in response to the delivered radiation. Thisinformation can then be incorporated into the medical management andtreatment of the patient to improve therapy outcomes and to mitigateside effects.

The amount of radiation used in photon radiation therapy is measured ingray (Gee), and varies depending on the type and stage of cancer beingtreated. For curative cases, the typical dose for a solid epithelialtumor ranges from 60 to 80 Gee, while lymphomas are treated with 20 to40 Gee. Preventative (adjuvant) doses are typically around 45 to 60 Gyin fractions of 1.8 to 2 Gy (e.g., for breast, head, and neck cancers).Radiation oncologists may consider other factors when selecting a dose,including whether the patient is receiving chemotherapy, patientcomorbidities, whether radiation therapy is being administered before orafter surgery, and the degree of success of surgery.

Delivery parameters of a prescribed dose are determined during treatmentplanning (e.g. as part of a dosimetry analysis or other process).Treatment planning is generally performed on dedicated computers usingspecialized treatment planning software. Depending on the radiationdelivery method, several angles or sources may be used to sum to thetotal necessary dose. A treatment planner generally seeks to design aplan that delivers a uniform prescription dose to the tumor andminimizes dose delivered to surrounding healthy tissues. The likelihoodof controlling or curing the disease and the probability of side effectis determined by evaluating dose and dose-volume criteria that have beenestablished through clinical experience and clinical trials.

The total dose delivered for a course of radiation therapy may bedelivered in a single dose or fractionated (spread out over time).Fractionation allows normal cells time to recover, while tumor cells aregenerally less efficient in repair between fractions. Fractionation alsoallows tumor cells that were in a relatively radiation-resistant phaseof the cell cycle during one treatment fraction to cycle into asensitive phase of the cycle before the next treatment fraction isdelivered. Similarly, tumor cells that were chronically or acutelyhypoxic (and therefore more radiation-resistant) may re-oxygenatebetween fractions, improving the tumor cell kill. Fractionation regimensare individualized between different radiation therapy centers and evenbetween individual doctors. The typical fractionation schedule foradults is 1.8 to 2 Gy per day, five days a week. In some cancer types,prolongation of the fraction schedule over too long can allow for thetumor to begin repopulating, and for these tumor types, includinghead-and-neck and cervical squamous cell cancers, radiation treatment ispreferably completed within a certain amount of time. For children, atypical fraction size may be approximately 1.5 to 1.8 Gy per day, assmaller fraction sizes are associated with reduced incidence andseverity of late effects in normal tissues.

In some cases, two fractions per day are used near the end of a courseof treatment. This schedule, known as a concomitant boost regimen orhyperfractionation, is used on tumors that regenerate more quickly whenthey are smaller. In particular, tumors in the head-and-neck demonstratethis behavior.

Recently hypofractionation has become more common. This is a radiationtreatment in which the total dose of radiation is divided into largedoses, and treatments are given less than once a day. Typical doses varysignificantly by cancer type, from approximately 3Gy per fraction toapproximately 20Gy per fraction. A hypofractionation approach generallyattempts to lessen the possibility of the cancer returning by not givingthe cells enough time to reproduce. For single dose delivery orhypofractionation extra care is often taking in localizing andimmobilizing the patient often with methods of stereotaxis.

With brachytherapy, implants can be continuously fractionated overminutes or hours, or they can be permanent seeds, which slowly deliverradiation continuously until they become inactive.

Magnetic resonance 1magmg can be used to assess inflammatory and otherresponses in human tissues and tumors to provide a better measure ofcell damage and tissue response than the physical dose distribution.Differences in radiosensitivity that may exist in the tumor or organmicroenvironment or genetically from patient to patient will beaccounted for with such a method.

Many types of MRI scans can assess inflammatory response andmorphological changes induced by ionizing radiation. Examples of MRIscans include basic MRI scans (e.g., T₁-weighted MRI T₂-weightedMRI,T*₂-weighted MRI, Spin density weighted MRI, and the like) andspecialized MRI scans (e.g., diffusion MRI, magnetization transfer MRI,T_(1ρ) MRI, Fluid attenuated inversion recovery, magnetic resonanceangiography, magnetic resonance gated intracranial CSF dynamics;magnetic resonance spectroscopy, magnetic resonance spectroscopicimaging, functional MRI, and the like).

T₁-weighted scans refer to a set of standard scans that depictdifferences in the spin-lattice (or T₁) relaxation time of varioustissues within the body. T₁-weighted images can be acquired using eitherspin echo or gradient-echo sequences. T₁-weighted contrast can beincreased with the application of an inversion recovery RF pulse.Gradient-echo based T₁-weighted sequences can be acquired very rapidlybecause of their ability to use short inter-pulse repetition times (TR).T₁-weighted sequences are often collected before and after infusion ofT₁-shortening MRI contrast agents. In the brain T₁-weighted scansprovide appreciable contrast between gray and white matter. In the body,T₁-weighted scans work well for differentiating fat from water, withwater appearing darker and fat brighter.

T₂-weighted scans refer to a set of standard scans that depictdifferences in the spin-spin (or T₂) relaxation time of various tissueswithin the body. Like the T₁-weighted scan, fat is differentiated fromwater. However, in T₂-weighted scans fat shows darker, and waterlighter. For example, in the case of cerebral and spinal study, the CSF(cerebrospinal fluid) will be lighter in T₂-weighted images. These scansare therefore particularly well suited to imaging edema, with long echotimes (TE) and long TR. Because the spin echo sequence is lesssusceptible to inhomogeneities in the magnetic field, these images havelong been a clinical workhorse.

T*₂ (pronounced “T 2 star”) weighted scans use a gradient echo (GRE)sequence, with long TE and long TR. The GRE sequence used does not havethe extra refocusing pulse used in spin echo so it is subject toadditional losses above the normal T₂ decay (referred to as T₂′). Theseadditional losses tend to make T*₂ more prone to susceptibility lossesat air-tissue boundaries, but can increase contrast for certain types oftissue, such as venous blood.

Spin density, which is also referred to as proton density, weightedscans are generally intended to have no contrast from either T₂ or T₁decay, with the only signal change coming from differences in the amountof available spins (hydrogen nuclei in water). This approach uses a spinecho or sometimes a gradient echo sequence, with short TE and long TR.

Diffusion MRI, a type of specialized MRI scan, measures the diffusion ofwater molecules m biological tissues. Clinically, diffusion MRI isuseful for the diagnoses of conditions (e.g., stroke) or neurologicaldisorders (e.g., Multiple Sclerosis), and helps improve understanding ofthe connectivity of white matter axons in the central nervous system. Inan isotropic medium (inside a glass of water for example), watermolecules naturally move randomly according to turbulence and Brownianmotion. In biological tissues, however, where the Reynolds number is lowenough for flows to be laminar, the diffusion may be anisotropic. Forexample, a molecule inside the axon of a neuron has a low probability ofcrossing the myelin membrane. Therefore the molecule moves principallyalong the axis of the neural fiber. If it is known that molecules in aparticular voxel diffuse principally in one direction, the assumptioncan be made that the majority of the fibers in this area are goingparallel to that direction.

The recent development of diffusion tensor imaging (DTI) enablesdiffusion to be measured in multiple directions and the fractionalanisotropy in each direction to be calculated for each voxel. Thisdevelopment can enable researchers to make brain maps of fiberdirections to examine the connectivity of different regions in the brain(using tractography) or to examine areas of neural degeneration anddemyelination in diseases like multiple sclerosis.

Another application of diffusion MRI is diffusion-weighted imaging(DWI). Following an ischemic stroke, DWI is highly sensitive to thechanges occurring in the lesion. It is speculated that increases inrestriction (barriers) to water diffusion, as a result of cytotoxicedema (cellular swelling), can be responsible for the increase in signalon a DWI scan. The DWI enhancement appears within 5-10 minutes of theonset of stroke symptoms (as compared with computed tomography, whichoften does not detect changes of acute infarct for up to 4-6 hours) andremains for up to two weeks. Coupled with imaging of cerebral perfusion,researchers can highlight regions of “perfusion/diffusion mismatch” thatmay indicate regions capable of salvage by reperfusion therapy.

Like many other specialized applications, this technique is usuallycoupled with a fast image acquisition sequence, such as echo planarimaging sequence.

Magnetization transfer (MT) refers to the transfer of longitudinalmagnetization from free water protons to hydration water protons in NMRand MRI. In magnetic resonance imaging of molecular solutions, such asprotein solutions, two types of water molecules, free (bulk) andhydration (bound), are found. Free water protons have faster averagerotational frequency and hence less fixed water molecules that may causelocal field inhomogeneity. Because of this uniformity, most free waterprotons have a resonance frequency lying narrowly around the normalproton resonance frequency of 63 MHz (at 1.5 teslas). This also resultsin slower transverse magnetization dephasing and hence longer T₂.Conversely, hydration water molecules are slowed down by interactionwith solute molecules and hence create field inhomogeneities that leadto wider resonance frequency spectrum.

In free liquids, protons, which may be viewed classically as smallmagnetic dipoles, exhibit translational and rotational motions. Thesemoving dipoles disturb the surrounding magnetic field however on longenough time-scales (which may be nanoseconds) the average field causedby the motion of protons is zero. This effect is known as “motionalaveraging” or narrowing and is characteristic of protons moving freelyin a liquid phase. On the other hand, protons bound to macromolecules,such as proteins, tend to have a fixed orientation and so the averagemagnetic field in close proximity to such structures does not average tozero. The result is a spatial pattern in the magnetic field that givesrise to a residual dipolar coupling (range of precession frequencies)for the protons experiencing the magnetic field. The wide frequencydistribution appears as a broad spectrum that may be several kHz wide.The net signal from these protons disappears very quickly, in inverseproportion to the width, due to the loss of coherence of the spins, i.e.T₂ relaxation. Due to exchange mechanisms, such as spin transfer orproton chemical exchange, the (incoherent) spins bound to themacromolecules continually switch places with (coherent) spins in thebulk media and establish a dynamic equilibrium.

Although there is generally no measurable signal from the bound spins,or the bound spins that exchange into the bulk media, their longitudinalmagnetization is preserved and may typically recover only via therelatively slow process of T₁ relaxation. If the longitudinalmagnetization of just the bound spins can be altered, then the effectcan be measured in the spins of the bulk media due to the exchangeprocesses. A magnetization transfer sequence applies radiofrequency (RF)saturation at a frequency that is far off resonance for the narrow lineof bulk water but still on resonance for the bound protons with aspectral linewidth on the order of kHz. The RF application causessaturation of the bound spins which exchange into the bulk water,resulting in a loss of longitudinal magnetization and hence signaldecrease in the bulk water, thereby providing an indirect measure ofmacromolecular content in tissue. Implementation of magnetizationtransfer involves choosing suitable frequency offsets and pulse shapesto saturate the bound spins sufficiently strongly, within the safetylimits of specific absorption rate for RF irradiation.

T_(1ρ) MRI generally relies upon the fact that molecules have a kineticenergy that is a function of the temperature and is expressed astranslational and rotational motions, and by collisions betweenmolecules. The moving dipoles disturb the magnetic field but are oftenextremely rapid so that the average effect over a long time-scale may bezero. However, depending on the time-scale, the interactions between thedipoles do not always average away. At the slowest extreme theinteraction time is effectively infinite and occurs where there arelarge, stationary field disturbances (e.g. a metallic implant). In thiscase the loss of coherence is described as a “static dephasing”. T*₂ isa measure of the loss of coherence in an ensemble of spins that includeall interactions (including static dephasing). T₂ is a measure of theloss of coherence that excludes static dephasing, using an RF pulse toreverse the slowest types of dipolar interaction. There is in fact acontinuum of interaction time-scales in a given biological sample andthe properties of the refocusing RF pulse can be tuned to refocus morethan just static dephasing. In general, the rate of decay of an ensembleof spins is a function of the interaction times and also the power ofthe RF pulse. Measurement of spin-lattice relaxation time in therotating frame occurring under the influence of RF, is known as T_(1ρ).It is similar to T₂ decay but with some slower dipolar interactionsrefocused as well as the static interactions, hence T_(1ρ)≥T₂.

Fluid attenuated inversion recovery (FLAIR) is an inversion-recoverypulse sequence used to null signal from fluids. For example, it can beused in brain imaging to suppress cerebrospinal fluid (CSF) so as tobring out the periventricular hyperintense lesions, such as multiplesclerosis (MS) plaques. By carefully choosing the inversion time TI (thetime between the inversion and excitation pulses), the signal from anyparticular tissue can be suppressed.

Magnetic resonance angiography (MRA) generates pictures of the arteriesto evaluate them for stenosis (abnormal narrowing) or aneurysms (vesselwall dilatations, at risk of rupture). MRA is often used to evaluate thearteries of the neck and brain, the thoracic and abdominal aorta, therenal arteries, and the legs (called a “run-off”). A variety oftechniques can be used to generate the pictures, such as administrationof a paramagnetic contrast agent (gadolinium) or using a technique knownas “flow-related enhancement” (e.g. 2D and 3D time-of-flight sequences),where most of the signal on an image is due to blood that recently movedinto that plane. Fast low angle shot (FLASH) MRI is a related technique.Techniques involving phase accumulation (known as phase contrastangiography) can also be used to generate flow velocity maps easily andaccurately. Magnetic resonance venography (MRV) is a similar procedurethat is used to image veins. In this method, the tissue is now excitedinferiorly, while signal is gathered in the plane immediately superiorto the excitation plane-thus imaging the venous blood that recentlymoved from the excited plane.

A magnetic resonance gated intracranial cerebrospinal fluid (CSF) orliquor dynamics (MR-GILD) technique is an MR sequence based on bipolargradient pulse used to demonstrate CSF pulsatile flow in ventricles,cisterns, aqueduct of Sylvius and entire intracranial CSF pathway. It isa method for analyzing CSF circulatory system dynamics in patients withCSF obstructive lesions such as normal pressure hydrocephalus. It alsoallows visualization of both arterial and venous pulsatile blood flow invessels without use of contrast agents.

Magnetic resonance spectroscopy (MRS) can be used to measure the levelsof different metabolites in body tissues. The MR signal produces aspectrum of resonances that correspond to different moleculararrangements of the isotope being “excited.” This signature can be usedto diagnose certain metabolic disorders, especially those affecting thebrain, and to provide information on tumor metabolism. Magneticresonance spectroscopic imaging (MRSI) combines both spectroscopic andimaging methods to produce spatially localized spectra from within thesample or patient. The spatial resolution is much lower (limited by theavailable SNR), but the spectra in each voxel contains information aboutmany metabolites. Because the available signal is used to encode spatialand spectral information, MRSI requires high SNR achievable only athigher field strengths (3 T and above).

Functional MRI (fMRI) measures signal changes in the brain that are dueto changing neural activity. The brain is scanned at low resolution butat a rapid rate (typically once every 2-3 seconds). Increases in neuralactivity cause changes in the MR signal via T*₂ changes. This mechanismis referred to as the blood-oxygen-level dependent (BOLD) effect.Increased neural activity causes an increased demand for oxygen, and thevascular system actually overcompensates for this, increasing the amountof oxygenated hemoglobin relative to deoxygenated hemoglobin. Becausedeoxygenated hemoglobin attenuates the MR signal, the vascular responseleads to a signal increase that is related to the neural activity. Theprecise nature of the relationship between neural activity and the BOLDsignal is a subject of current research. The BOLD effect also allows forthe generation of high resolution 3D maps of the venous vasculaturewithin neural tissue.

While a BOLD signal is the most common method employed for neurosciencestudies in human subjects, the flexible nature of MR imaging providesmeans to sensitize the signal to other aspects of the blood supply.Alternative techniques employ arterial spin labeling (ASL) or weight theMRI signal by cerebral blood flow (CBF) and cerebral blood volume (CBV).The CBV method requires injection of a class of MRI contrast agents thatare now in human clinical trials. Because this method has been shown tobe far more sensitive than the BOLD technique in preclinical studies, itmay potentially expand the role of fMRI in clinical applications. TheCBF method provides more quantitative information than the BOLD signal,albeit at a significant loss of detection sensitivity.

The acute and late responses of human tissues to ionizing radiation canbe imaged with MRI techniques during treatment to assess the trueradiosensitivity modified response of tissue and tumor to the deliveredionizing radiation. For example, epithelial surfaces may sustain damagefrom radiation therapy and internal surfaces may thicken which can bedetected and measured with T₁, T₂, T*₂, or spin density imaging. Inother examples, imaging can detect irradiated tissues that tend tobecome less elastic over time due to a diffuse scarring process.Fibrotic response can be imaged, as well as Lymphedema, which is acondition of localized fluid retention and tissue swelling resultingfrom damage to the lymphatic system sustained during radiation therapy.Lymphedema is the most commonly reported complication in breastradiation therapy patients who receive adjuvant axillary radiotherapyfollowing surgery to clear the axillary lymph nodes).

Edema is part of the general inflammation that occurs from radiationdamage of cells, as further explained below, and can be directlymeasured with T₁ and T₂ weighted MRI consistent with implementations ofthe current subject matter which includes techniques, methods, systems,apparatus, articles, etc. relating to tracking of radiation damage viainflammatory response expressed as edema. Quantitative measurements ofinflammation response can result from measures the swelling due to acuteinflammation inside a patient's tissue with MRI radiography.

Inflammation is part of the complex biological response of vasculartissues to harmful stimuli, such as ionizing radiation. Other stimulisuch as cancerous tumor invasion, pathogens, damaged cells or irritantscan also cause inflammation, but baseline measurements and assessmentcan be separated from ionizing radiation induced inflammation.Inflammation is a protective attempt by the organism to remove theinjurious stimuli, dead cells or matter and to initiate the healingprocess. Inflammation is considered as a mechanism of innate immunity orsensitivity to the stimulus causing it. It is also an importantmechanism for the healing of wounds and infections. However, chronicinflammation can also lead to a host of diseases, such as hay fever,periodontitis, atherosclerosis, rheumatoid arthritis, and even cancer(e.g., gallbladder carcinoma). Therefore, inflammation is closelyregulated by the body.

Inflammation can be classified as either acute or chronic. Acuteinflammation is the initial response of the body to harmful stimuli andis achieved by the increased movement of plasma and leukocytes(especially granulocytes) from the blood into the injured tissues. Acascade of biochemical events propagates and matures the inflammatoryresponse, involving the local vascular system, the immune system, andvarious cells within the injured tissue. Prolonged inflammation, knownas chronic inflammation, leads to a progressive shift in the type ofcells present at the site of inflammation and is characterized bysimultaneous destruction and healing of the tissue from the inflammatoryprocess.

The classic signs and symptoms of acute inflammation are redness,swelling, heat, pain, and loss of tissue function. Any sign may beobserved in specific instances, but no single sign must, as a matter ofcourse, be present. Typically inflammation is observed visually andqualitatively by external examination by a medical practitioner. Theclassic signs appear when acute inflammation occurs on a body's surface,whereas acute inflammation of internal organs may not result in the fullset. Pain generally results only where the appropriate sensory nerveendings exist in the inflamed area. For example, acute inflammation ofthe lung (pneumonia) does not cause pain unless the inflammationinvolves the parietal pleura, which does have pain-sensitive nerveendings.

Acute inflammation 1s a short-term process, usually appearing within afew minutes or hours and ceasing upon the removal of the injuriousstimulus. Redness and heat are due to increased blood flow at body coretemperature to the inflamed site, swelling is caused by accumulation offluid, and pain is due to release of chemicals that stimulate nerveendings. Loss of function can have multiple causes.

Cells present in all tissues, such as for example resident macrophages,dendritic cells, histiocytes, Kupffer cells, mastocytes, etc. typicallyinitiate the process of acute inflammation. These cells present on theirsurfaces certain receptors named pattern recognition receptors (PRRs),which recognize molecules that are broadly shared by pathogens butdistinguishable from host molecules, collectively referred to aspathogen-associated molecular patterns (PAMPs). At the onset of aninfection, burn, or other injuries, these cells undergo activation(i.e., one of their PRRs recognize a PAMP) and release inflammatorymediators responsible for the clinical signs of inflammation.Vasodilation and its resulting increased blood flow causes the redness(rubor) and increased heat (calor). Increased permeability of the bloodvessels results in an exudation (leakage) of plasma proteins and fluidinto the tissue (edema), which manifests itself as swelling (tumor).Some of the released mediators such as bradykinin increase thesensitivity to pain (hyperalgesia, dolor). The mediator molecules alsoalter the blood vessels to permit the migration of leukocytes, mainlyneutrophils, outside of the blood vessels (extravasation) into thetissue. The neutrophils migrate along a chemotactic gradient created bythe local cells to reach the site of injury. The loss of function(functio laesa) is probably the result of a neurological reflex inresponse to pain.

In addition to cell-derived mediators, several acellular biochemicalcascade systems consisting of preformed plasma proteins act in parallelto initiate and propagate the inflammatory response. These include thecomplement system activated by bacteria, and the coagulation andfibrinolysis systems activated by necrosis, e.g. a burn or a trauma.

The acute inflammatory response requires constant stimulation to besustained. Inflammatory mediators have short half lives and are quicklydegraded in the tissue. Hence, acute inflammation generally ceases anddiminishes once the stimulus has been removed.

The exudative component involves the movement of plasma fluid,containing important proteins such as fibrin and immunoglobulins(antibodies), into inflamed tissue. This movement is achieved via thechemically induced dilation and increased permeability of blood vessels,which results in a net loss of blood plasma. The increased collection offluid into the tissue causes it to swell (edema). This extravasatedfluid is funneled by lymphatics to the regional lymph nodes, flushingbacteria along to start the recognition and attack phase of the adaptiveimmune system.

Acute inflammation is characterized by marked vascular changes,including but not necessarily limited to vasodilation, increasedpermeability, and increased blood flow, which are induced by the actionsof various inflammatory mediators. Vasodilation occurs first at thearteriole level, progressing to the capillary level, and can bring abouta net increase in the amount of blood present, which can in turn causethe redness and heat of inflammation. Increased permeability of thevessels results in the movement of plasma into the tissues, withresultant stasis due to the increase in the concentration of the cellswithin blood. Enlarged vessels packed with cells typically characterizethis condition. Stasis allows leukocytes to marginate (move) along theendothelium, a process critical to their recruitment into the tissues.Normal flowing blood prevents this, as the shearing force along theperiphery of the vessels moves cells in the blood into the middle of thevessel.

Inflammation orchestrates the microenvironment around tumors, which cancontribute to proliferation, survival and migration. Cancer cells useselectins, chemokines and their receptors for invasion, migration,metastasis, and the like. On the other hand, many cells of the immunesystem contribute to cancer immunology, suppressing cancer. Molecularintersection between receptors of steroid hormones, which have importanteffects on cellular development, and transcription factors that play keyroles in inflammation, such as NF-KB, may mediate some of the mostcritical effects of inflammatory stimuli on cancer cells. This capacityof a mediator of inflammation to influence the effects of steroidhormones in cells is very likely to affect carcinogenesis in someexamples. On the other hand, due to the modular nature of many steroidhormone receptors, this interaction may offer ways to interfere withcancer progression, for example through targeting of a specific proteindomain in a specific cell type. Such an approach may limit side effectsthat are unrelated to the tumor of interest, and may help preserve vitalhomeostatic functions and developmental processes in the organism.

The outcome in a particular circumstance will be determined by thetissue in which the injury has occurred and the injurious agent that iscausing it. Possible outcomes to inflammation can include resolution,fibrosis, abcess formation, chronic inflammation, swelling, and thelike.

Resolution is the complete restoration of the inflamed tissue back to anormal status. Inflammatory measures such as vasodilation, chemicalproduction, and leukocyte infiltration cease, and damaged parenchymalcells regenerate. In situations where limited or short livedinflammation has occurred this is usually the outcome.

Large amounts of tissue destruction, or damage in tissues unable toregenerate, may not be completely regenerated by the body. Fibrosisrefers to fibrous scarring which occurs in these areas of damage to forma scar composed primarily of collagen. The scar will not contain anyspecialized structures, such as parenchymal cells. Accordingly,functional impairment may occur.

Abscess formation includes formation of a cavity containing pus, whichis an opaque liquid containing dead white blood cells and bacteria withgeneral debris from destroyed cells.

If an injurious agent causing acute inflammation persists, chronicinflammation will ensue. This process, marked by inflammation lastingmany days, months or even years, may lead to the formation of a chronicwound. Chronic inflammation is characterized by the dominating presenceof macrophages in the injured tissue. These cells are powerful defensiveagents of the body, but the toxins they release (including reactiveoxygen species) are injurious to the organism's own tissues as well asinvading agents. Consequently, chronic inflammation is almost alwaysaccompanied by tissue destruction.

In medical parlance, swelling, turgescence, or tumefaction is atransient abnormal enlargement of a body part or area not caused byproliferation of cells. It is caused by accumulation of fluid intissues. It can occur throughout the body (generalized), or a specificpart or organ can be affected (localized). Swelling is considered one ofthe five characteristics of inflammation along with pain, heat, redness,and loss of function. A body part may swell in response to injury,infection, or disease. Swelling can occur if the body is not circulatingfluid well.

Generalized swelling, or massive edema (also called anasarca) is acommon sign in severely ill people. Although slight edema may bedifficult to detect to the untrained eye, especially in an overweightperson, massive edema is generally very obvious. Edema (AmericanEnglish) or oedema (British English), formerly known as dropsy orhydropsy, is an abnormal accumulation of fluid beneath the skin or inone or more cavities of the body that produces swelling. Generally, theamount of interstitial fluid is determined by the balance of fluidhomeostasis, and increased secretion of fluid into the interstitium orimpaired removal of this fluid may cause edema.

Cutaneous edema is referred to as “pitting” when, after pressure isapplied to a small area, the indentation persists for some time afterthe release of the pressure. Peripheral pitting edema is the more commontype, resulting from water retention and can be caused by systemicdiseases, pregnancy in some women, either directly or as a result ofheart failure, or local conditions such as varicose veins,thrombophlebitis, insect bites, and dermatitis. Non-pitting edema isobserved when the indentation does not persist. It is associated withsuch conditions as lymphedema, lipedema and myxedema.

Causes of edema which are generalized to the whole body can cause edemain multiple organs and peripherally. For example, severe heart failurecan cause pulmonary edema, pleural effusions, ascites and peripheraledema.

Although a low plasma oncotic pressure is widely cited for the edema ofnephrotic syndrome, most physicians note that the edema may occur beforethere is any significant protein in the urine (proteinuria) or fall inplasma protein level. Fortunately there is another explanationavailable. Most forms of nephrotic syndrome are due to biochemical andstructural changes in the basement membrane of capillaries in the kidneyglomeruli, and these changes occur, if to a lesser degree, in thevessels of most other tissues of the body. Thus the resulting increasein permeability that leads to protein in the urine can explain the edemaif all other vessels are more permeable as well.

As well as the previously mentioned conditions, edemas often occurduring the late stages of pregnancy in some women. This is more commonwith those of a history of pulmonary problems or poor circulation alsobeing intensified if arthritis is already present in that particularwoman. Women that already have arthritic problems most often have toseek medical help for pain caused from over-reactive swelling. Edemasthat occur during pregnancy are usually found in the lower part of theleg, usually from the calf down.

An edema can occur in specific organs as part of inflammations,tendinitis, or pancreatitis, for example. Certain organs develop edemathrough tissue specific mechanisms. For example, cerebral edema isextracellular fluid accumulation in the brain. It can occur in toxic orabnormal metabolic states and conditions such as systemic lupus orreduced oxygen at high altitudes. It causes drowsiness or loss ofconsciousness. Pulmonary edema occurs when the pressure in blood vesselsin the lung is raised because of obstruction to remove blood via thepulmonary veins. This is usually due to failure of the left ventricle ofthe heart. It can also occur in altitude sickness or on inhalation oftoxic chemicals. Pulmonary edema produces shortness of breath. Pleuraleffusions may occur when fluid also accumulates in the pleural cavity.Edema may also be found in the cornea of the eye with glaucoma, severeconjunctivitis or keratitis or after surgery. Such edemas may result inthe patient seeing colored haloes around bright lights. Edemasurrounding the eyes is called periorbital edema or eye puffiness. Theperiorbital tissues are most noticeably swollen immediately afterwaking, perhaps as a result of the gravitational redistribution of fluidin the horizontal position.

Common appearances of cutaneous edema are observed with mosquito bites,spider bites, bee stings (wheal and flare), and skin contact withcertain plants such as Poison Ivy or Western Poison Oak, the latter ofwhich are termed contact dermatitis. Another cutaneous form of edema ismyxedema, which is caused by increased deposition of connective tissue.In myxedema (and a variety of other rarer conditions) edema is caused byan increased tendency of the tissue to hold water within itsextracellular space. In myxedema this is because of an increase inhydrophilic carbohydrate-rich molecules (perhaps mostly hyaluronan)deposited in the tissue matrix. Edema forms more easily in dependentareas in the elderly (sitting in chairs at home or on airplanes) andthis is not well understood. Estrogens alter body weight in part throughchanges in tissue water content. There may be a variety of poorlyunderstood situations in which transfer of water from tissue matrix tolymphatics is impaired because of changes in the hydrophilicity of thetissue or failure of the “wicking” function of terminal lymphaticcapillaries.

In lymphedema, abnormal removal of interstitial fluid is caused byfailure of the lymphatic system. This may be due to obstruction from,for example, pressure from a cancer or enlarged lymph nodes, destructionof lymph vessels by radiotherapy, or infiltration of the lymphatics byinfection (such as elephantiasis). It is most commonly due to a failureof the pumping action of muscles due to immobility, most strikingly inconditions such as multiple sclerosis, or paraplegia. Lymphatic returnof fluid is also dependent on a pumping action of structures known aslymph hearts. It has been suggested that the edema that occurs in somepeople following use of aspirin-like cyclo-oxygenase inhibitors such asibuprofen or indomethacin may be due to inhibition of lymph heartaction.

Factors that can contribute to the formation of edema include increasedhydrostatic pressure, reduced oncotic pressure within blood vessels,increased tissue oncotic pressure, increased blood vessel wallpermeability (e.g., inflammation), obstruction of fluid clearance viathe lymphatic system, and changes in the water retaining properties ofthe tissues themselves. Raised hydrostatic pressure often reflectsretention of water and sodium by the kidney.

Generation of interstitial fluid is regulated by the forces of theStarling equation, which can be represented by the is the net fluidmovement between compartments Jv as follows:

J _(v) =K _(f) F _(D)  (1)

where K_(f) is the filtration coefficient (a proportionality constant),and the net driving force F_(D) can be represented as

F _(D)=[P _(c) −P _(i)]−σ[π_(c)−π_(i)]  (2)

where Pc is the capillary hydrostatic pressure, P_(i) is theinterstitial hydrostatic pressure, π_(c) is the capillary oncoticpressure, π_(i) is the interstitial oncotic pressure, and σ is thereflection coefficient.

Hydrostatic pressure within blood vessels tends to cause water to filterout into the tissue. This leads to a difference in protein concentrationbetween blood plasma and tissue. As a result, the oncotic pressure ofthe higher level of protein in the plasma tends to draw water back intothe blood vessels from the tissue. Starling's equation states that therate of leakage of fluid is determined by the difference between the twoforces and also by the permeability of the vessel wall to water, whichdetermines the rate of flow for a given force imbalance. Most waterleakage occurs in capillaries or post capillary venules, which have asemi-permeable membrane wall that allows water to pass more freely thanprotein. The protein is said to be reflected and the efficiency ofreflection is given by a reflection constant of up to 1. If the gapsbetween the cells of the vessel wall open up then permeability to wateris increased first, but as the gaps increase in size, permeability toprotein also increases with a fall in reflection coefficient.

Changes in values of the variables in Starling's equation can contributeto the formation of edemas either by an increase in hydrostatic pressurewithin the blood vessel, a decrease in the oncotic pressure within theblood vessel or an increase in vessel wall permeability. The latter hastwo effects. It allows water to flow more freely and it reduces theoncotic pressure difference by allowing protein to leave the vessel moreeasily.

The Dose-volume histogram (DVH) us a concept used in radiation treatmentplanning. DVHs were introduced by Michael Goitein, who also introducedradiation therapy concepts such as the “beam's-eye-view,” “digitallyreconstructed radiograph,” and uncertainty/error in planning andpositioning, among others, and Verhey in 1979 in a publication byShipley et al. A DVH summarizes 3D dose distributions in a graphical 2Dformat. In modern radiation therapy, 3D dose distributions are typicallycreated in a computerized treatment planning system based on a 3Dreconstruction of a CT or MR scan. The “volume” referred to in DVHanalysis can be a target of radiation treatment, a healthy organ nearbya target, or an arbitrary structure.

DVHs can be visualized in either of two ways: differential DVHs orcumulative DVHs. A DVH is created by first determining the size of thedose bins of the histogram. Bins can be of arbitrary size, for example,0 to 1 Gy, 1.001 to 2 Gy, 2.001 to 3 Gy, etc. In a differential DVH, baror column height indicates the volume of structure receiving a dosegiven by the bin. Bin doses are along the horizontal axis, and structurevolumes (either percent or absolute volumes) are on the vertical.

The differential DVH takes the appearance of a typical histogram. Thecumulative DVH is plotted with bin doses along the horizontal axis, aswell. However, the column height of the first bin (for example, 0 to 1Gy) represents the volume of structure receiving greater than or equalto that dose. The column height of the second bin (for example, 1.001-2Gy) represents the volume of structure receiving greater than or equalto that dose, etc. With very fine (small) bin sizes, the cumulative DVHtakes on the appearance of a smooth line graph. The lines always slopeand start from top-left to bottom-right. For a structure receiving avery homogenous dose, for example, 100% of the volume receiving exactly10 Gy, the cumulative DVH will appear as a horizontal line at the top ofthe graph, at 100% volume as plotted vertically, with a vertical drop at10 Gy on the horizontal axis.

Cumulative DVHs are overwhelmingly used and preferred over differentialDVHs. The DVH is ubiquitous in the medical specialty of radiationoncology. A DVH used clinically usually includes all structures andtargets of interest in the radiotherapy plan, with each line plotted ina different color representing a different structure. The vertical axisis almost always plotted as percent volume (rather than absolutevolume), as well. Clinical studies commonly employ DVH metrics tocorrelate with patient toxicities and outcomes.

A drawback of the DVH methodology is that it offers no spatialinformation. In other words, a DVH does not show where within astructure a dose is received. Also, DVHs from initial radiotherapy plansrepresent the doses relative to structures at the start of radiationtreatment. As treatment progresses and time elapses, if there arechanges (i.e. if patients lose weight, if tumors shrink, if organschange shape, etc.), the original DVH loses validity, for example due toa change in the denominator for one or more of the calculations inherentin the presented data. The spatial attributes of a dose distribution canbe visualized by scrolling through orthogonal images with overlain dosedistributions.

The current practice of radiation oncology correlates the probability ofcontrolling or curing a tumor and the probability of inducing a deadlyor debilitating side effect in a healthy or functional organ with dataderived from a dose volume histogram and point, planar, or volumetric ordose distributions computed from a radiation therapy treatment plan.

Ionizing radiation dose is the energy per unit mass of ionizingradiation delivered to a patient or object. It is intended to be aquantitative measure of the amount of damage caused by the radiation tothe DNA or other critical molecules of cancerous or targeted cells, andunavoidable irradiated healthy or functional cells. However, the 4 R'sof radiobiology which are known to vary in different individuals due togenetic, morphologic, and pathologic reasons can greatly influence theactual damage caused by the radiation to the DNA or other criticalmolecules of cancerous or targeted cells, and unavoidably irradiatedhealthy or functional cells.

When cells are irradiated and damaged or killed by ionizing radiation,this stimulus induces an inflammation response in the irradiatedtissues. Because this response is mediated by actual damage to the cellsand tissues, it is a more direct measure of actual damage and cell deaththan delivered physical ionizing radiation dose.

The inflammation response can be measured as acute edema producedfollowing or during radiation delivery. The change in MR imaging signalof tissues before and after the application of ionizing radiation is adirect quantitative measure of the increase in fluid, seen as a decreasein T1 weighted MR scans and a corresponding increase in T₂ (or T*₂)weighted MR scans of the same anatomy in the same patient. This decreasein T₁, increase in T₂, or both, is a direct quantitative measure of theinflammation. The time from delivery of stimulus and the length of thescan can also be accounted for in the measure to allow for the buildupor decay of induced edema. This signal intensity can then be representedas an inflammation distribution to replace the dose distribution forevaluation of delivered cellular damage. Similarly, inflammation volumehistograms can be produced and correlated to patient outcomes andtoxicity. Such tools provide a better predictor of probability of tumorcontrol or cure as well as probability of normal or healthy tissuetoxicity as the inflammation, as measured by induced edema, is in directresponse to the ionizing radiation stimulus.

In further implementations of the current subject matter, observation ofinflammation outside of regions intended to receive damage from ionizingradiation can be used as a safety feature to alert clinical users tounintended or accidental delivery of ionizing radiation.

Inflammation response changes the fluid content of the tissue receivingradiation damage. This increase in fluid changes the material in thebeam path such that the effective atomic number is different andpositions at which different types of radiation are absorbed can alsochange. For example, an increase in fluid content can result in less“fat-like” material (e.g. CH₂) and more “water-like” material in thebeam path. In proton therapy or heavy ion therapy, stopping powers forthe delivered beam constituents can thereby be changed at a local level,thereby changing the range of the Bragg peak and thus changing thedelivered dose distribution. Likewise, an increase in hydrogen contentcan change the dose from a neutron beam. Thus, quantitative assessmentof edema with MRI scans can be used to improve the ability to computedose for proton, heavy ion, and neutron therapy as well.

Implementations of the current subject matter can be realized using asystem or other apparatus capable of capturing MRI images of at leastpart of a patient with at least some degree of concurrency with deliveryof one or more radiation beams. In other words, one or more MRI imagescan be captured during delivery of a fraction of a radiation therapydose. This technology can also be referred to as “intra-fraction” MRI.In other implementations of the current subject matter, MRI can be usedperiodically, optionally but not necessarily within radiation fractions,to collected differential data characterizing a change in edema in apatient during a course of treatment. For example, a baseline scan canbe performed of an area being treated, and then one or more additionalscans can be collected over the course of treatment to quantify changesin edema in the treated tissues and those tissues surrounding thetreated tissue or otherwise affected by one or more radiation beams. Theone or more additional scans can optionally include one or more of ascan or scans performed during at least one fraction, a scan or scansperformed between two or more fractions in a series of fractions, a scanor scans performed at some other interval (which can be fixed orvariable), and the like.

A non-limiting example of a system capable of intra-fraction MRI imagingis described in co-owned co-owned U.S. Pat. No. 7,907,987, thedisclosure of which is incorporated herein by reference in its entirety.FIG. 1 through FIG. 5 show views 100, 200, 300, 400, 500, respectively,illustrating examples of features that can be included in such a system.A main magnet Helmholtz coil pair 115 of an MRI machine can be designedas a split solenoid so that a patient couch 130 runs through acylindrical bore in the middle of the magnets and a radiation source 120(e.g., a linear accelerator, a radioisotope source, etc. capable ofdelivering one or more of radioisotope beams, proton beams, heavy ionbeams, neutron beams, X-rays, or the like) can be aimed down the gapbetween the two solenoidal sections 115 at a patient 135 on the patientcouch 130. The split solenoidal MRI magnets 115 can remain stationarywhile the radiation source 120, which can include a multi-leafcollimator intensity modulated radiation therapy (IMRT) unit, is rotatedaxially around the couch on a gantry 125. More than one radiation source120 can be beneficially employed. The patient 135 is positioned on thepatient couch 130 for simultaneous (or at least approximately concurrentor at least approximately simultaneous) imaging and treatment.

As shown in FIG. 5, the radiation source 120 with a multi-leafcollimator can contain a radioisotopic source 515 (or other radiationsource) which can optionally be collimated with a fixed primarycollimator 520, a secondary doubly divergent multileaf collimator 525,and tertiary multi-leaf collimator 530 to block interleaf leakage fromthe secondary multi-leaf collimator 525. It will be understood thatother systems capable of producing MRI imagery either during a fractionor otherwise substantially concurrently with the fraction (e.g. within ashort period of time before after, or during a fraction) can also beuseful in implementing the current subject matter. Additionally, inimplementations of the current subject matter in which intra-fractionMRI scans are used, conventional MRI systems that do not incorporateconcurrent radiation delivery can also be used.

FIG. 6 and FIG. 7 show two MRI scan images 600, 700 of same part of asubject patient taken closely in time. The scan image 600 of FIG. 6shows a T₁-weightedscan in which areas containing more free hydrogen(e.g. tissues having higher water content) are represented more darklythan areas containing more fixed hydrogen (e.g. fatty tissue). The scanimage 700 of FIG. 7 shows a T₂-weighted scan in which areas containingmore fixed hydrogen (e.g. fatty tissue) are represented more darkly thanareas containing more free hydrogen (e.g. tissues having higher watercontent). The scan images 600, 700 show a section through the subjectpatient's abdomen and show the liver 602, kidneys 604, and spinal column606 among other features. The liver 602 contains a high amount of fattytissue, and is therefore less dark in the scan image 600 showing theT₁-weighted scan result than in the scan image 607 showing theT₂-weighted scan result. Similarly, the spinal column is lighter in FIG.6 than in FIG. 7 while the kidneys, having a larger water content, aredarker in FIG. 6 than in FIG. 7. Also depicted in FIG. 6 and FIG. 7 is aradiation pathway 610 over which radiation treatment was delivered tothe patient. As seen in both FIG. 6 and FIG. 7, the scan images 600, 700indicate an increase in fluid along the radiation pathway 610, whichappears as a darker line in the lighter liver 602 in the T₁-weightedscan of FIG. 6 and as a lighter line in the darker liver in theT₂-weighted scan of FIG. 7. This increased fluid is the result of edemacaused by cell damage in tissues affected by the radiation treatment.

Prior to the present disclosure, a conventional approach to observationsof such edema was to ignore or attempt to correct for this “artifact”that generally considered as an interference to analysis of underlyingpathologies that necessitated the radiation treatment. In contrast, thecurrent subject matter utilizes a quantification of edema based on oneor more MRI scans of a treated area of a patient to at least estimate aneffect of a radiation treatment dose on both a target structure (e.g. atumor or other diseased tissue) and the surrounding tissues. The edemaquantified in this manner is generally considered to be acute, transientedema resulting from cell death in the tissue through which the beam hadpassed.

In practice, implementations of the current subject matter can includequantification of a ratio of T₁-weighted and T₂-weighted scans todetermine, or at least estimate, a free hydrogen ratio as a function ofspatial location within a patient's tissues. Increases in the estimatedfree hydrogen ratio can be interpreted as an indicator of increasededema in the patient's tissues. In this manner changes in edema can beused as a proxy for estimation of an amount of cell damage or death isoccurring in a given tissue region of the patient. As noted above, celldamaged or destruction by radiation-induced (as well as other) traumaresults in initiator cells (e.g. macrophages, dendritic cells,histiocytes, Kupffer cells, mastocytes, etc.) releasing inflammatorymediators responsible for the clinical signs of inflammation, includingbut not limited to edema (exudation of plasma proteins and fluid intothe tissue). This fluid exudation can be detected, at least on adifferential basis, consistent with implementations of the currentsubject matter by using MRI scans to detect changes in free hydrogencontent in tissues. It is possible to characterize such changes usingone or more of the scans discussed above. In other examples, two or morescans can be combined to create a ratio metric representative of thefree hydrogen content in a patient's tissues as a function of spatialposition with the tissues.

Consistent with one or more implementations of the current subjectmatter, a method as illustrated in the process flow chart 800 of FIG. 8can include the following features. At 802, a subsequent edema analysis(e.g. a subsequent MRI-based edema analysis) performed after or duringat least part of a course of radiation treatment are compared to abaseline edema analysis (e.g. a baseline MRI-based edema analysis)performed previous to the subsequent edema analysis to estimate a changein edema in patient tissues resulting from the course of radiationtreatment. In some implementations of the current subject matter, thesubsequent edema analysis and the baseline edema analysis can be MRIscans, which can provide estimates of fluid content in cells.

As discussed above, for example, the baseline and subsequent edemaanalyses can each include one or more MRI scans. In some implementationsof the current subject matter, the one or more MRI scans can includeboth T₁-weighted and T₂-weighted scans, and a ratio of the results ofthese scans can be prepared for each of the baseline and subsequentscan. The change in edema can be derived (e.g. estimated, calculated,determined, etc.) based on a differential analysis of the subsequentscan and the baseline scan to determine changes occurring during thecourse of radiation treatment. In some examples, an amount of freehydrogen can be quantified in the subsequent scan relative to thebaseline scan, and a change in the relative amount of free hydrogen canbe used as a proxy for the change in edema in the patient's tissue.

A baseline scan can act as a reference for comparison with the one ormore subsequent MRI scans taken during or after at least one radiationfraction delivered to the patient in the course of radiation treatment.In other words, the baseline scan accounts for the presence of existingedema, for example edema resulting from original pathologies, othertrauma, etc. At least one subsequent MRI scan is taken during the courseof treatment (e.g. one or more of intra-fraction or inter-fraction MRIscans), and changes occurring in the patient's tissue between thebaseline and subsequent scans can be quantified. In some examples, thisquantifying can be accomplished via a differential imaging approach toindicate changes in intensity of MRI signals from patient tissue.

A single type of MRI scan can be used for the baseline and at least onesubsequent scan, and changes in the MRI response to this kind of scancan be quantified between the baseline and subsequent scan.Alternatively, as noted above, each scan can include a ratio of two ormore types of scans, such as for example T₁-weighted and T₂-weightedscans. Because edema generally result in an increase in fluid as normalcell damage or cell death recovery mechanisms involve flushing of deador damaged cell material away via liquids that have a higher water (andtherefore high free hydrogen) content. In some variations, a baselinescan can be taken prior to any treatment and then used in comparisonswith subsequent scans taken during or between radiation dose fractionsdelivered to the patient. In other variations, a series of scans can beused, and differential analysis can be applied between two or more scansin the series, possible but not necessarily using a scan collected priorto the commencement of a course of radiation treatment as the baselinescan.

At 804, an edema to delivered dose correlation is derived based on thechange in edema in the patient tissue correlated with a delivered doseof radiation during the course of radiation treatment. In other words,one or more calculations or models of physical dose delivery can beapplied to derive (e.g. estimate, calculate, determine, etc.) one ormore of an amount of radiation actually delivered to the patient tissue,an expected amount of radiation delivered to the patient tissue, or thelike. The derived amount of radiation actually delivered or expected tohave been delivered can optionally be based on one or more inputs. Insome variations, a pre-radiation treatment plan can provide these data.In other variations, a combined MRI and radiation delivery approach(e.g. as described in co-owned U.S. Pat. No. 7,907,987) can be used incalculating a more accurate measure of received doses of radiation todiseased tissue and other tissue structures based on intra-fractionmotions of the patient, the patient's organs, etc.

The correlating of the change in edema in the patient tissue with thedelivered dose (or the expected delivered dose) can involve quantifyinghow the change in edema corresponds to an expected outcome for thediseased tissue and surrounding tissues relative to an expected value(e.g. an expected response of tissue to the amount of deliveredradiation). The expected value can be calculated empirically,experimentally, through the application of one or more theoreticalmodels, or the like, or through the combination of one or more suchapproaches.

At 806, one or more clinical actions are performed based on the edema todelivered dose correlation. The clinical actions can include one or moreof a variety of actions. For example, if edema a patient experiences, inparticular edema in tissue structures other than the target diseasedtissue, exceeds an expected value by more than a threshold amount, thecourse of treatment can be stopped for further analysis, the radiationdelivery system can be inspected to ascertain any malfunctioningcomponents, a clinician can be alerted by a user interface or some otherautomated method, an amount of radiation delivered in a next fractioncan be reduced, etc. In other examples, if the edema a patientexperiences, in particular edema in target diseased tissue, is less thanan expected value by more than a threshold amount, the course oftreatment can likewise be stopped for further analysis, the radiationdelivery system can be inspected to ascertain any malfunctioningcomponents, a clinician can be alerted by a user interface or some otherautomated method, an amount of radiation delivered in a next fractioncan be increased (assuming, for example that edema experienced by thepatient in tissue structures other than the target diseased tissue iswithin some acceptable limit), etc.

As discussed above, MRI scan data analyzed differentially over someperiod of time that includes at least one delivery of a radiationtherapy dose can be used to derive at least an estimate of amount ofcell death or damage occurring in the scanned tissue. Such data can beexpressed in a variety of ways, including but not limited to a visualdepiction, a numerical expression, or the like representing intensity asa function of location within a patient's tissues. For example, in thecase of a ratio of T₁-weighted and T₂-weighted scans used as a proxy forfree hydrogen content in scanned tissues, the differential changes inthe ratio of these two scans can be presented as a function of location.This presentation can include use of voxels on a 2D map or other imageof a part of the patient's tissues in the vicinity of the targeteddiseased tissue to visually depict cell death or damage occurring over acourse of treatment.

Increasing ratios of free hydrogen can be used as a proxy for increasingamounts of damaged tissue in a given location, which can be clinicallyuseful as a virtual, relative dosimeter for absorbed active radiationdose. In this manner, a measure can be provided of how much of atreatment impact the radiation therapy has had on the targeted diseasedtissue how severely other surrounding tissues have been impacted, etc.Accordingly, implementations of the current subject matter can assist inmedically managing a patient undergoing radiation treatment. Comparisonof the “expected” outcomes of a dosimetry plan with actual observedchanges in edema can allow a clinician to better estimate how a specificpatient is responding to the specific course of radiation treatment.

FIG. 9 shows a schematic diagram of a system 900 having one or morefeatures in common with implementations of the current subject matter. Acomputing system 902 can be in communication with an MRI system 904, andoptionally with a radiation delivery system 906. A user interface canoptionally include displays, user input devices, etc. as well as otherexamples discussed below for conveying information to a clinician orother user and/or for receiving information inputs. The computing system902 can optionally be part of or otherwise integrated into the MRIsystem 904 and/or to the radiation delivery system. In the example ofFIG. 1 through FIG. 5, the computing system 902, the MRI system 904, andthe radiation delivery system 906 can all be integrated. In someexamples, the radiation delivery system 906 can include its owncomputing system, such as for example a dose planning system runningdose planning software. Communication of data between the variouscomponents of the system 900 can be accomplished over any data transferconnections (networks, computer buses, etc.). The computing system 902can optionally include a programmable processor that executes one ormore software modules that implement one or more of the featuresdiscussed above.

One or more aspects or features of the subject matter described hereincan be realized in digital electronic circuitry, integrated circuitry,specially designed application specific integrated circuits (ASICs),field programmable gate arrays (FPGAs) computer hardware, firmware,software, and/or combinations thereof. These various aspects or featurescan include implementation in one or more computer programs that areexecutable and/or interpretable on a programmable system including atleast one programmable processor, which can be special or generalpurpose, coupled to receive data and instructions from, and to transmitdata and instructions to, a storage system, at least one input device,and at least one output device.

These computer programs, which can also be referred to programs,software, software applications, applications, components, or code,include machine instructions for a programmable processor, and can beimplemented in a high-level procedural language, an object-orientedprogramming language, a functional programming language, a logicalprogramming language, and/or in assembly/machine language. As usedherein, the term “machine-readable medium” refers to any computerprogram product, apparatus and/or device, such as for example magneticdiscs, optical disks, memory, and Programmable Logic Devices (PLDs),used to provide machine instructions and/or data to a programmableprocessor, including a machine-readable medium that receives machineinstructions as a machine-readable signal. The term “machine-readablesignal” refers to any signal used to provide machine instructions and/ordata to a programmable processor. The machine-readable medium can storesuch machine instructions non-transitorily, such as for example as woulda non-transient solid-state memory or a magnetic hard drive or anyequivalent storage medium. The machine-readable medium can alternativelyor additionally store such machine instructions in a transient manner,such as for example as would a processor cache or other random accessmemory associated with one or more physical processor cores.

To provide for interaction with a user, one or more aspects or featuresof the subject matter described herein can be implemented on a computerhaving a display device, such as for example a cathode ray tube (CRT) ora liquid crystal display (LCD) or a light emitting diode (LED) monitorfor displaying information to the user and a keyboard and a pointingdevice, such as for example a mouse or a trackball, by which the usermay provide input to the computer. Other kinds of devices can be used toprovide for interaction with a user as well. For example, feedbackprovided to the user can be any form of sensory feedback, such as forexample visual feedback, auditory feedback, or tactile feedback; andinput from the user may be received in any form, including, but notlimited to, acoustic, speech, or tactile input. Other possible inputdevices include, but are not limited to, touch screens or othertouch-sensitive devices such as single or multi-point resistive orcapacitive trackpads, voice recognition hardware and software, opticalscanners, optical pointers, digital image capture devices and associatedinterpretation software, and the like. A computer remote from ananalyzer can be linked to the analyzer over a wired or wireless networkto enable data exchange between the analyzer and the remote computer(e.g. receiving data at the remote computer from the analyzer andtransmitting information such as calibration data, operating parameters,software upgrades or updates, and the like) as well as remote control,diagnostics, etc. of the analyzer.

The subject matter described herein can be embodied in systems,apparatus, methods, and/or articles depending on the desiredconfiguration. The implementations set forth in the foregoingdescription do not represent all implementations consistent with thesubject matter described herein. Instead, they are merely some examplesconsistent with aspects related to the described subject matter.Although a few variations have been described in detail above, othermodifications or additions are possible. In particular, further featuresand/or variations can be provided in addition to those set forth herein.For example, the implementations described above can be directed tovarious combinations and subcombinations of the disclosed featuresand/or combinations and subcombinations of several further featuresdisclosed above. In addition, the logic flows depicted in theaccompanying figures and/or described herein do not necessarily requirethe particular order shown, or sequential order, to achieve desirableresults. Other implementations may be within the scope of the followingclaims.

1-20. (canceled)
 21. A system comprising: an MRI system; a radiationsource; and at least one non-transitory machine-readable medium storinginstructions which, when executed by a programmable processor, cause theprogrammable processor to perform operations comprising: capturing abaseline MRI scan and, during a treatment, a subsequent MRI scan;comparing a baseline edema analysis utilizing the baseline MRI scan witha subsequent edema analysis utilizing the subsequent MRI scan toestimate a change in edema in patient tissues; and alerting a clinicianor stopping treatment when the estimated change in edema exceeds anexpected value.
 22. A system as in claim 21, wherein the baseline MRIscan and the subsequent MRI scan comprise at least one of: a T₁-weightedMRI scan, a T₂-weighted MRI scan, a ratio of T₁-weighted MRI toT₂-weighted MRI scan results, and an MRI response ratio.
 23. A system asin claim 21, wherein the comparing comprises quantifying changes in freehydrogen content.
 24. A system as in claim 21, the operations furthercomprising generating, at a display, a visual depiction of an estimateof an amount of cell death in the patient tissues.
 25. A system as inclaim 24, the visual depiction including the use of voxels on a 2D map.26. A system as in claim 24, wherein the visual depiction comprises adifferential change in a ratio of T₁-weighted MRI to T₂-weighted MRIscans and the differential change is presented as a function oflocation.
 27. A computer program product comprising a non-transitorymachine-readable medium storing instructions which, when executed by aprogrammable processor, cause the programmable processor to performoperations comprising: capturing a baseline MRI scan and, during atreatment, a subsequent MRI scan; comparing a baseline edema analysisutilizing the baseline MRI scan with a subsequent edema analysisutilizing the subsequent MRI scan to estimate a change in edema inpatient tissues; and alerting a clinician or stopping treatment when theestimated change in edema exceeds an expected value.
 28. A computerprogram product as in claim 27, wherein the baseline MRI scan and thesubsequent MRI scan comprise at least one of: a T₁-weighted MRI scan, aT₂-weighted MRI scan, a ratio of T₁-weighted MRI to T₂-weighted MRI scanresults, and an MRI response ratio.
 29. A computer program product as inclaim 27, wherein the comparing comprises quantifying changes in freehydrogen content.
 30. A computer program product as in claim 27, theoperations further comprising generating, at a display, a visualdepiction of an estimate of an amount of cell death in the patienttissues.
 31. A computer program product as in claim 30, the visualdepiction including the use of voxels on a 2D map.
 32. A computerprogram product as in claim 30, wherein the visual depiction comprises adifferential change in a ratio of T₁-weighted MRI to T₂-weighted MRIscans and the differential change is presented as a function oflocation.